Squalene epoxidase promotes hepatocellular carcinoma development by
activating STRAP transcription and TGF-β/SMAD signaling
Background and Purpose Squalene epoxidase (SQLE) is a key enzyme
involved in cholesterol biosynthesis, but increasing evidence reveals
that SQLE is abnormally expressed in some types of malignant tumors, and
the underlying mechanism remains poorly understood. Experimental
Approach Bioinformatics analysis and RNA sequencing were applied to
detect to differentially expressed genes in clinical HCC tumors.
AnnexinV-FITC/PI, EdU assay, transwell, IHC staining, cytoskeleton
F-actin filaments assay, RNA sequencing, dual-luciferase reporters and
HE staining were evaluated to investigate the pharmacological effects
and possible mechanisms of SQLE. Key Results We found that SQLE
expression is specifically elevated in HCC tumors, correlating with poor
clinical outcomes. SQLE promoted HCC growth, EMT, and metastasis both in
vitro and in vivo. In contrast, silencing of SQLE expression prevented
HCC development. Both RNA-seq and functional experiments revealed that
the protumorigenic effect of SQLE on HCC is closely related to the
activation of cellular TGF-β/SMAD signaling, but interestingly, the
stimulatory effect of SQLE on TGF-β/SMAD signaling and HCC development
is also critically dependent on STRAP, a serine and threonine kinase.
SQLE expression is well correlated with STRAP in HCC, and further, to
amplify TGF-β/SMAD signaling, SQLE even transcriptionally increased
STRAP gene expression mediated by the trans-acting factor AP-2α.
Finally, as a chemical inhibitor of SQLE, NB-598 markedly inhibited HCC
cell growth and tumor development in mouse models. Conclusions and
Implications Taken together, SQLE serves as an oncogene in HCC
development by activating TGF-β/SMAD signaling, and targeting SQLE could
be useful in drug development and therapy for HCC.